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Chapter 4 - The Effect of Endocrine Disruptors and Environmental and Lifestyle Factors on the Sperm Epigenome

Published online by Cambridge University Press:  24 May 2020

By
Viviane Santana ,
Albert Salas-Huetos ,
Emma R. James  and
Douglas T. Carrell
Edited by
R. John Aitken ,
David Mortimer  and
Gabor Kovacs
R. John Aitken
Affiliation:
University of Newcastle, New South Wales
David Mortimer
Affiliation:
Oozoa Biomedical Inc, Vancouver
Gabor Kovacs
Affiliation:
Epworth Healthcare Melbourne
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Summary

The sperm epigenome is unique and of profound clinical importance based on its role in influencing embryogenesis. Potentially, the sperm epigenome can also be of importance to the clinician and toxicologist in assessing the effects of environmental exposures and lifestyle factors on spermatogenesis and sperm function, since the sperm epigenome contains historical markers of spermatogenesis, as well as programmatic factors of early embryonic development. Various industrial and agricultural chemicals are implicated in affecting male fertility, and recent studies have begun to evaluate the effects of these chemicals on the sperm epigenome. Additionally, lifestyle factors, such as obesity and advanced paternal age at the time of conception, are also being shown to affect the sperm epigenome. This chapter evaluates such factors and their effects on the sperm epigenome, highlighting the possible effects on both the father and potential progeny.

Keywords

endocrine disruptorsperm epigeneticsDNA methylationhistonesnoncoding RNAslifestyleenvironmentagingsmoking
Type
Chapter
Information
Male and Sperm Factors that Maximize IVF Success , pp. 41 - 58
Publisher: Cambridge University Press
Print publication year: 2020

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References

Waddington, C. H. (1942) The epigenotype. Endeavour, 18–20.Google Scholar
Skinner, M. K., Manikkam, M. and Guerrero-Bosagna, C. (2010) Epigenetic transgenerational actions of environmental factors in disease etiology. Trends Endocrinol Metab 21:214–222.CrossRefGoogle ScholarPubMed
Meldrum, D. R., et al. (2016) Aging and the environment affect gamete and embryo potential: can we intervene? Fertil Steril 105:548–559.Google Scholar
Skakkebaek, N. E., et al. (2016) Male reproductive disorders and fertility trends: influences of environment and genetic susceptibility. Physiol Rev 96:55–97.CrossRefGoogle ScholarPubMed
Stuppia, L., Franzago, M., Ballerini, P., Gatta, V. and Antonucci, I. (2015) Epigenetics and male reproduction: the consequences of paternal lifestyle on fertility, embryo development, and children lifetime health. Clin Epigenetics 7:120.Google Scholar
Carrell, D. T. (2012) Epigenetics of the male gamete. Fertil Steril 97:267–274.CrossRefGoogle ScholarPubMed
Castillo, J., Jodar, M. and Oliva, R. (2018) The contribution of human sperm proteins to the development and epigenome of the preimplantation embryo. Hum Reprod Update 24:535–555.CrossRefGoogle Scholar
Denomme, M. M., McCallie, B. R., Parks, J. C., Schoolcraft, W. B. and Katz-Jaffe, M. G. (2017) Alterations in the sperm histone-retained epigenome are associated with unexplained male factor infertility and poor blastocyst development in donor oocyte IVF cycles. Hum Reprod 32:2443–2455.CrossRefGoogle ScholarPubMed
Aston, K. I., Uren, P. J., Jenkins, T. G., Horsager, A., Cairns, B. R., Smith, A. D., et al. (2015) Aberrant sperm DNA methylation predicts male fertility status and embryo quality. Fertil Steril 104:1388–1397.Google Scholar
Ge, S. Q., Lin, S. L., Zhao, Z. H. and Sun, Q. Y. (2017) Epigenetic dynamics and interplay during spermatogenesis and embryogenesis: implications for male fertility and offspring health. Oncotarget 8:53804–53818.Google Scholar
McSwiggin, H. M. and O’Doherty, A. M. (2018) Epigenetic reprogramming during spermatogenesis and male factor infertility. Reproduction 156:R9–R21.Google Scholar
Schagdarsurengin, U., Paradowska, A. and Steger, K. (2012) Analysing the sperm epigenome: roles in early embryogenesis and assisted reproduction. Nat Rev Urol 9:609–619.CrossRefGoogle ScholarPubMed
Urdinguio, R. G., et al. (2015) Aberrant DNA methylation patterns of spermatozoa in men with unexplained infertility. Hum Reprod 30:1014–1028.Google Scholar
Jones, P. A. (2012) Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet 13:484–492.CrossRefGoogle ScholarPubMed
Jenkins, T. G., Aston, K. I., James, E. R. and Carrell, D. T. (2017) Sperm epigenetics in the study of male fertility, offspring health, and potential clinical applications. Syst Biol Reprod Med 63:69–76.CrossRefGoogle Scholar
Rajender, S., Avery, K. and Agarwal, A. (2011) Epigenetics, spermatogenesis and male infertility. Mutat Res 727:62–71.Google Scholar
Jenkins, T. G. and Carrell, D. T. (2011) The paternal epigenome and embryogenesis: poising mechanisms for development. Asian J Androl 13:76–80.Google Scholar
Ankolkar, M., et al. (2012) Methylation analysis of idiopathic recurrent spontaneous miscarriage cases reveals aberrant imprinting at H19 ICR in normozoospermic individuals. Fertil Steril 98:1186–1192.Google Scholar
Wykes, S. M. and Krawetz, S. A. (2003) The structural organization of sperm chromatin. J Biol Chem 278:29471–29477.CrossRefGoogle ScholarPubMed
Carrell, D. T., Emery, B. R. and Hammoud, S. (2007) Altered protamine expression and diminished spermatogenesis: what is the link? Hum Reprod Update 13:313–327.Google Scholar
Carrell, D. T. and Liu, L. (2001) Altered protamine 2 expression is uncommon in donors of known fertility, but common among men with poor fertilizing capacity, and may reflect other abnormalities of spermiogenesis. J Androl 22:604–610.Google Scholar
Aoki, V. W., et al. (2005) DNA integrity is compromised in protamine-deficient human sperm. J Androl 26:741–748.CrossRefGoogle ScholarPubMed
Aoki, V. W., Liu, L. and Carrell, D. T. (2005) Identification and evaluation of a novel sperm protamine abnormality in a population of infertile males. Hum Reprod 20:1298–1306.Google Scholar
Torregrosa, N., et al. (2006) Protamine 2 precursors, protamine 1/protamine 2 ratio, DNA integrity and other sperm parameters in infertile patients. Hum Reprod 21:2084–2089.Google Scholar
Hammoud, S. S., et al. (2009) Distinctive chromatin in human sperm packages genes for embryo development. Nature 460:473–478.CrossRefGoogle ScholarPubMed
Brykczynska, U., et al. (2010) Repressive and active histone methylation mark distinct promoters in human and mouse spermatozoa. Nat Struct Mol Biol 17:679–687.Google Scholar
Kouzarides, T. (2007) Chromatin modifications and their function. Cell 128:693–705.CrossRefGoogle ScholarPubMed
Krawetz, S. A., et al. (2011) A survey of small RNAs in human sperm. Hum Reprod 26:3401–3412.CrossRefGoogle ScholarPubMed
Jodar, M., et al. (2013) The presence, role and clinical use of spermatozoal RNAs. Hum Reprod Update 19:604–624.Google Scholar
Jodar, M., et al.(2015) Absence of sperm RNA elements correlates with idiopathic male infertility. Sci Transl Med 7:295re296.Google Scholar
Sharma, U., et al. (2018) Small RNAs are trafficked from the epididymis to developing mammalian sperm. Dev Cell 46:481–494. e486.Google Scholar
Conine, C. C., Sun, F., Song, L., Rivera-Pérez, J. A. and Rando, O. J. (2018) Small RNAs gained during epididymal transit of sperm are essential for embryonic development in mice. Dev Cell 46:470–480. e473.Google Scholar
de Mateo, S. and Sassone-Corsi, P. (2014) Regulation of spermatogenesis by small non-coding RNAs: role of the germ granule. Semin Cell Dev Biol 29:84–92.Google Scholar
Zheng, K. and Wang, P. J. (2012) Blockade of pachytene piRNA biogenesis reveals a novel requirement for maintaining post-meiotic germ line genome integrity. PLoS Genet 8:e1003038.Google Scholar
Ferreira, H. J., et al. (2014) Epigenetic loss of the PIWI/piRNA machinery in human testicular tumorigenesis. Epigenetics 9:113–118.Google Scholar
Capra, E., et al. (2017) Small RNA sequencing of cryopreserved semen from single bull revealed altered miRNAs and piRNAs expression between high- and low-motile sperm populations. BMC Genomics 18:14.Google Scholar
Abu-Halima, M., et al. (2014) Panel of five microRNAs as potential biomarkers for the diagnosis and assessment of male infertility. Fertil Steril 102:989–997. e981.Google Scholar
Bansal, S. K., Gupta, N., Sankhwar, S. N. and Rajender, S. (2015) Differential genes expression between fertile and infertile spermatozoa revealed by transcriptome analysis. PLoS One 10:e0127007.Google Scholar
Salas-Huetos, A., et al. (2015) Spermatozoa from patients with seminal alterations exhibit a differential micro-ribonucleic acid profile. Fertil Steril 104:591–601.Google Scholar
Salas-Huetos, A., et al.(2016) Spermatozoa from normozoospermic fertile and infertile individuals convey a distinct miRNA cargo. Andrology 4:1028–1036.Google Scholar
Carlsen, E., Giwercman, A., Keiding, N. and Skakkebaek, N. E. (1992) Evidence for decreasing quality of semen during past 50 years. BMJ 305:609–613.Google Scholar
Sikka, S. C. and Wang, R. (2008) Endocrine disruptors and estrogenic effects on male reproductive axis. Asian J Androl 10:134–145.CrossRefGoogle ScholarPubMed
Bibbo, M., Haenszel, W. M., Wied, G. L., Hubby, M. and Herbst, A. L. (1978) A twenty-five-year follow-up study of women exposed to diethylstilbestrol during pregnancy. N Engl J Med 298:763–767.CrossRefGoogle ScholarPubMed
Dallinga, J. W., et al. (2002) Decreased human semen quality and organochlorine compounds in blood. Hum Reprod 17:1973–1979.CrossRefGoogle ScholarPubMed
Guo, Y. L., Hsu, P. C., Hsu, C. C. and Lambert, G. H. (2000) Semen quality after prenatal exposure to polychlorinated biphenyls and dibenzofurans. Lancet 356:1240–1241.CrossRefGoogle ScholarPubMed
Ohlson, C. G. and Hardell, L. (2000) Testicular cancer and occupational exposures with a focus on xenoestrogens in polyvinyl chloride plastics. Chemosphere 40:1277–1282.CrossRefGoogle ScholarPubMed
Schwartz, G. G. (2002) Hypothesis: does ochratoxin A cause testicular cancer? Cancer Causes Control 13:91–100.CrossRefGoogle ScholarPubMed
Weidner, I. S., Moller, H., Jensen, T. K. and Skakkebaek, N. E. (1998) Cryptorchidism and hypospadias in sons of gardeners and farmers. Environ Health Perspect 106:793–796.CrossRefGoogle ScholarPubMed
Eertmans, F., Dhooge, W., Stuyvaert, S. and Comhaire, F. (2003) Endocrine disruptors: effects on male fertility and screening tools for their assessment. Toxicol in Vitro 17:515–524.CrossRefGoogle ScholarPubMed
Anway, M. D., Cupp, A. S., Uzumcu, M. and Skinner, M. K. (2005) Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 308:1466–1469.CrossRefGoogle ScholarPubMed
Anway, M. D., Memon, M. A., Uzumcu, M. and Skinner, M. K. (2006) Transgenerational effect of the endocrine disruptor vinclozolin on male spermatogenesis. J Androl 27:868–879.Google Scholar
Anway, M. D. and Skinner, M. K. (2008) Transgenerational effects of the endocrine disruptor vinclozolin on the prostate transcriptome and adult onset disease. Prostate 68:517–529.Google Scholar
Anway, M. D. and Skinner, M. K. (2008) Epigenetic programming of the germ line: effects of endocrine disruptors on the development of transgenerational disease. Reprod Biomed Online 16:23–25.Google Scholar
Brieno-Enriquez, M. A., et al. (2015) Exposure to endocrine disruptor induces transgenerational epigenetic deregulation of microRNAs in primordial germ cells. PLoS One 10:e0124296.Google Scholar
Guerrero-Bosagna, C., Settle, M., Lucker, B. and Skinner, M. K. (2010) Epigenetic transgenerational actions of vinclozolin on promoter regions of the sperm epigenome. PLoS One 5(9).Google Scholar
Manikkam, M., Guerrero-Bosagna, C., Tracey, R., Haque, M. M. and Skinner, M. K. (2012) Transgenerational actions of environmental compounds on reproductive disease and identification of epigenetic biomarkers of ancestral exposures. PLoS One 7:e31901.CrossRefGoogle ScholarPubMed
Manikkam, M., Tracey, R., Guerrero-Bosagna, C. and Skinner, M. K. (2013) Plastics derived endocrine disruptors (BPA, DEHP and DBP) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations. PLoS One 8:e55387.Google Scholar
Nilsson, E. E. and Skinner, M. K. (2015) Environmentally induced epigenetic transgenerational inheritance of reproductive disease. Biol Reprod 93:145.Google Scholar
Stouder, C. and Paoloni-Giacobino, A. (2010) Transgenerational effects of the endocrine disruptor vinclozolin on the methylation pattern of imprinted genes in the mouse sperm. Reproduction 139:373–379.Google Scholar
Stouder, C. and Paoloni-Giacobino, A. (2011) Specific transgenerational imprinting effects of the endocrine disruptor methoxychlor on male gametes. Reproduction 141:207–216.CrossRefGoogle ScholarPubMed
Svechnikov, K., Izzo, G., Landreh, L., Weisser, J. and Söder, O. (2010) Endocrine disruptors and Leydig cell function. J Biomed Biotechnol 2010:684504.Google Scholar
Sharpe, R. M. (2006) Pathways of endocrine disruption during male sexual differentiation and masculinization. Best Pract Res Clin Endocrinol Metab 20:91–110.Google Scholar
Masoro, E. J. (2011) A. S. Handbook of the biology of aging. J Psychosom Res 23.Google Scholar
Paul, C. and Robaire, B. (2013) Ageing of the male germ line. Nat Rev Urol 10:227–234.Google Scholar
Miller, B., et al. (2011) Meta-analysis of paternal age and schizophrenia risk in male versus female offspring. Schizophr Bull 37:1039–1047.Google Scholar
Jenkins, T. G., Aston, K. I. and Carrell, D. T. (2018) Sperm epigenetics and aging. Transl Androl Urol 7:S328–S335.Google Scholar
Jenkins, T. G., Aston, K. I., Pflueger, C., Cairns, B. R. and Carrell, D. T. (2014) Age-associated sperm DNA methylation alterations: possible implications in offspring disease susceptibility. PLoS Genet 10:e1004458.Google Scholar
Atse, S., et al. (2016) Paternal age effects on sperm FOXK1 and KCNA7 methylation and transmission into the next generation. Hum Mol Genet 25:4996–5005.Google Scholar
Levine, H., et al. (2017) Temporal trends in sperm count: a systematic review and meta-regression analysis. Hum Reprod Update 23:646–659.Google Scholar
Abu-Musa, A. A., Nassar, A. H., Hannoun, A. B. and Usta, I. M. (2007) Effect of the Lebanese civil war on sperm parameters. Fertil Steril 88:1579–1582.Google Scholar
Clarke, R. N., Klock, S. C., Geoghegan, A. and Travassos, D. E. (1999) Relationship between psychological stress and semen quality among in-vitro fertilization patients. Hum Reprod 14:753–758.CrossRefGoogle ScholarPubMed
DeStefano, F., Annest, J. L., Kresnow, M. J., Schrader, S. M. and Katz, D. F. (1989) Semen characteristics of Vietnam veterans. Reprod Toxicol 3:165–173.Google Scholar
Fenster, L., et al. (1997) Effects of psychological stress on human semen quality. J Androl 18:194–202.Google Scholar
Lampiao, F. (2009) Variation of semen parameters in healthy medical students due to exam stress. Malawi Med J 21:166–167.Google Scholar
Nargund, V. H. (2015) Effects of psychological stress on male fertility. Nat Rev Urol 12:373–382.CrossRefGoogle ScholarPubMed
Roberts, A. L., et al. (2018) Exposure to childhood abuse is associated with human sperm DNA methylation. Transl Psychiatry 8:194.Google Scholar
Dickson, D. A., et al. (2018) Reduced levels of miRNAs 449 and 34 in sperm of mice and men exposed to early life stress. Transl Psychiatry 8:101.Google Scholar
Gapp, K., et al. (2014) Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice. Nat Neurosci 17:667–669.CrossRefGoogle ScholarPubMed
Rodgers, A. B., Morgan, C. P., Leu, N. A. and Bale, T. L. (2015) Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress. Proc Natl Acad Sci USA 112:13699–13704.CrossRefGoogle ScholarPubMed
Swan, S. H., Elkin, E. P. and Fenster, L. (2000) The question of declining sperm density revisited: an analysis of 101 studies published 1934–1996. Environ Health Perspect 108:961–966.Google Scholar
Deng, Z., et al. (2016) Association between air pollution and sperm quality: A systematic review and meta-analysis. Environ Pollut 208:663–669.Google Scholar
Lafuentem, R., Garcia-Blaquez, N., Jacquemin, B. and Checa, M. A. (2016) Outdoor air pollution and sperm quality. Fertil Steril 106:880–896.Google Scholar
Leiser, C. L., Hanson, H. A., Sawyer, K., Steenblik, J., Al-Dulaimi, R., et al. (2019) Acute effects of air pollutants on spontaneous pregnancy loss: a case-crossover study. Fertil Steril 111(2):341–347.Google Scholar
Consales, C., et al. (2016) Exposure to persistent organic pollutants and sperm DNA methylation changes in Arctic and European populations. Environ Mol Mutagen 57:200–209.Google Scholar
Giahi, L., Mohammadmoradi, S., Javidan, A. and Sadeghi, M. R. (2016) Nutritional modifications in male infertility: a systematic review covering 2 decades. Nutr Rev 74:118–130.Google Scholar
Salas-Huetos, A., Bullo, M. and Salas-Salvado, J. (2017) Dietary patterns, foods and nutrients in male fertility parameters and fecundability: a systematic review of observational studies. Hum Reprod Update 23:371–389.Google Scholar
Salas-Huetos, A., et al. (2018) The effect of nutrients and dietary supplements on sperm quality parameters: a systematic review and meta-analysis of randomized clinical trials. Adv Nutr 9:833–848.Google Scholar
Lambrot, R., et al. (2013) Low paternal dietary folate alters the mouse sperm epigenome and is associated with negative pregnancy outcomes. Nat Commun 4: 2889.CrossRefGoogle ScholarPubMed
Aarabi, M., et al. (2018) Testicular MTHFR deficiency may explain sperm DNA hypomethylation associated with high dose folic acid supplementation. Hum Mol Genet 27:1123–1135.Google Scholar
Aarabi, M., et al. (2015) High-dose folic acid supplementation alters the human sperm methylome and is influenced by the MTHFR C677T polymorphism. Hum Mol Genet 24:6301–6313.Google Scholar
Chan, D., et al. (2017) Stability of the human sperm DNA methylome to folic acid fortification and short-term supplementation. Hum Reprod 32:272–283.Google Scholar
Xue, J., et al. (2018) Impact of vitamin D depletion during development on mouse sperm DNA methylation. Epigenetics 13:959–974.Google Scholar
Salas-Huetos, A., et al. (2018) Effect of nut consumption on semen quality and functionality in healthy men consuming a Western-style diet: a randomized controlled trial. Am J Clin Nutr 108:953–962.Google Scholar
Ramaraju, G. A., Teppale, S., Prathigudupu, K., Kalagara, K., Thota, S., Kota, M. et al. (2018) Association between obesity and sperm quality. Andrologia 50(3).Google Scholar
Craig, J. R., Jenkins, T. G., Carrell, D. T. and Hotaling, J. M. (2017) Obesity, male infertility, and the sperm epigenome. Fertil Steril 107:848–859.CrossRefGoogle ScholarPubMed
Raad, G., et al. (2017) Paternal obesity: how bad is it for sperm quality and progeny health? Basic Clin Androl 27:20.CrossRefGoogle ScholarPubMed
Fullston, T., et al. (2013) Paternal obesity initiates metabolic disturbances in two generations of mice with incomplete penetrance to the F2 generation and alters the transcriptional profile of testis and sperm microRNA content. FASEB J 27:4226–4243.Google Scholar
Soubry, A., et al. (2016) Obesity-related DNA methylation at imprinted genes in human sperm: results from the TIEGER study. Clin Epigenetics 8:51.Google Scholar
Sharma, R., Harlev, A., Agarwal, A. and Esteves, S. C. (2016) Cigarette smoking and semen quality: a new meta-analysis examining the effect of the 2010 World Health Organization laboratory methods for the examination of human semen. Eur Urol 70:635–645.Google Scholar
Polyzos, A., Schmid, T. E., Pina-Guzman, B., Quintanilla-Vega, B. and Marchetti, F. (2009) Differential sensitivity of male germ cells to mainstream and sidestream tobacco smoke in the mouse. Toxicol Appl Pharmacol 237:298–305.Google Scholar
Marczylo, E. L., Amoako, A. A., Konje, J. C., Gant, T. W. and Marczylo, T. H. (2012) Smoking induces differential miRNA expression in human spermatozoa: a potential transgenerational epigenetic concern? Epigenetics 7:432–439.Google Scholar
Hamad, M. F., et al. (2018) The status of global DNA methylation in the spermatozoa of smokers and non-smokers. Reprod Biomed Online 37:581–589.Google Scholar
Jenkins, T. G., et al. (2017) Cigarette smoking significantly alters sperm DNA methylation patterns. Andrology 5:1089–1099.Google Scholar
Alkhaled, Y., Laqqan, M., Tierling, S., Lo Porto, C., Amor, H. and Hammadeh, M.E. (2018) Impact of cigarette-smoking on sperm DNA methylation and its effect on sperm parameters. Andrologia, January.Google Scholar
Ricci, E., et al. (2017) Semen quality and alcohol intake: a systematic review and meta-analysis. Reprod Biomed Online 34:38–47.Google Scholar
Ouko, L. A., et al. (2009) Effect of alcohol consumption on CpG methylation in the differentially methylated regions of H19 and IG-DMR in male gametes: implications for fetal alcohol spectrum disorders. Alcohol Clin Exp Res 33:1615–1627.Google Scholar
Knezovich, J. G. and Ramsay, M. (2012) The effect of preconception paternal alcohol exposure on epigenetic remodeling of the h19 and rasgrf1 imprinting control regions in mouse offspring. Front Genet 3:10.CrossRefGoogle ScholarPubMed
Lee, H. J., et al. (2013) Transgenerational effects of paternal alcohol exposure in mouse offspring. Animal Cells and Systems 17:429–434.Google Scholar

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